More than just a pretty face? The relationship between immune function and perceived facial attractiveness.

It has long been hypothesized that attractiveness provides a cue to a target's health and immunocompetence. However, much of the research testing this hypothesis has relied on a small number of indirect proxies of immune function, and the results of this research have been mixed. Here, we build on this past research, examining the relationship between target attractiveness and (i) self-reported health, (ii) in vivo measures of inflammation and white blood cell count/composition, and (iii) in vitro tests of targets' immune function, including (c1) leucocyte proliferation in response to immunological stimulants, (c2) phagocytosis of Escherichia coli bioparticles, (c3) NK cell-mediated lysis of target tumour cells, and (c4) Staphylococcus aureus growth in isolated plasma. Results revealed multiple, sometimes sex-differentiated, relationships between targets' immune function and others' perceptions of their attractiveness. Together, this work suggests complex, often sex-differentiated relationships between immune function, health, and attractiveness.

Imatinib methanesulfonate reduces hippocampal amyloid-ß and restores cognitive function following repeated endotoxin exposure.

Alzheimer's disease (AD) is characterized, in part, by atrophy of the adult brain and increased presence of extracellular amyloid-beta (Aß) plaques. Previous studies in our lab have shown that peripheral inflammation can lead to increased central Aß and deficits in learning and memory. In order to determine whether Aß accumulation in the brain is responsible for the learning deficits, we attempted to decrease peripheral production of Aß in order to reduce central Aß accumulation. It has previously been shown that Aß is produced in large quantities in the liver, and is transferred across the blood-brain barrier (BBB). Recent research has shown that peripheral treatment with imatinib methanesulfonate salt (IM), known to interfere with the interaction between gamma (γ)-secretase and the γ-secretase activating protein (GSAP), decreases the cleavage of peripheral amyloid precursor protein into Aß. Because IM poorly penetrates the BBB, we hypothesized that co-administration of IM with LPS would decrease peripheral production of Aß in the presence of LPS-induced inflammation, leading to a decrease in Aß accumulation in the hippocampus. We show that peripheral IM treatment eliminates hippocampal Aß elevation that follows LPS-induced peripheral inflammation. Importantly, IM also eliminates the cognitive impairment seen following seven consecutive days of LPS administration, implicating Aß peptides as a likely cause of these cognitive deficits.

L-Deprenyl reverses age-associated decline in splenic norepinephrine, interleukin-2 and interferon-γ production in old female F344 rats.

UNLABELLED: Aging in female rats is associated with cessation of reproductive cycles, development of mammary cancer, and increased incidence of autoimmune diseases. Previously, we demonstrated an age-related decline in sympathetic noradrenergic (NA) innervation in the spleen and lymph nodes of female F344 rats accompanied by significantly reduced natural killer cell activity, interleukin (IL)-2 and interferon (IFN)-γ production, and T- and B-cell proliferation, suggesting possible links between sympathetic activity and immunosenescence. OBJECTIVES: The aim of this study is to investigate the effects of L-(-)-deprenyl, a monoamine oxidase-B inhibitor, on the sympathetic nervous system and cell-mediated immune responses in old female rats. METHODS: Low doses of L-deprenyl (0.25 or 1.0 mg/kg body weight, BW) were administered intraperitoneally to 19- to 21-month-old female F344 rats for 8 weeks. To assess the stereoselectivity of the effects of deprenyl on splenic sympathetic activity and immune responses, the D-enantiomer (D-(+)-deprenyl; 1.0 mg/kg BW) was also included in the studies. Norepinephrine (NE) concentration and content, and mitogen-induced T-cell proliferation and cytokine production were assessed in the splenocytes after deprenyl treatment. RESULTS: Treatment with L-deprenyl reversed the age-related decrease in NE concentration and content and IFN-γ production, and increased IL-2 production in the spleen while D-deprenyl did not affect the age-associated reduction in splenic NE levels or cytokine production. CONCLUSIONS: These findings demonstrate that L-deprenyl exerts neurorestorative and immunostimulatory effects on the sympathetic nervous system and cell-mediated immune responses during aging and provides evidence for a causal relationship between some aspects of immunosenescence and the age-related decline in sympathetic nerves in the spleens of female F344 rats.

A Synthetic Formula Amino Acid Diet Leads to Microbiome Dysbiosis, Reduced Colon Length, Inflammation, and Altered Locomotor Activity in C57BL/6J Mice.

The effects of synthetic, free-amino acid diets, similar to those prescribed as supplements for (phenylketonuria) PKU patients, on gut microbiota and overall health are not well understood. In the current, multidisciplinary study, we examined the effects of a synthetically-derived, low-fiber, amino acid diet on behavior, cognition, gut microbiome composition, and inflammatory markers. A cohort of 20 male C57BL/6J mice were randomly assigned to either a standard or synthetic diet (n = 10) at post-natal day 21 and maintained for 13 weeks. Sequencing of the 16S rRNA gene from fecal samples revealed decreased bacterial diversity, increased abundance of bacteria associated with disease, such as Prevotella, and a downward shift in gut microbiota associated with fermentation pathways in the synthetic diet group. Furthermore, there were decreased levels of short chain fatty acids and shortening of the colon in mice consuming the synthetic diet. Finally, we measured TNF-α, IL-6, and IL-10 in serum, the hippocampus, and colon, and found that the synthetic diet significantly increased IL-6 production in the hippocampus. These results demonstrate the importance of a multidisciplinary approach to future diet and microbiome studies, as diet not only impacts the gut microbiome composition but potentially systemic health as well.

Peripheral bacterial endotoxin administration triggers both memory consolidation and reconsolidation deficits in mice.

Peripherally administered inflammatory stimuli, such as lipopolysaccharide (LPS), induce the synthesis and release of proinflammatory cytokines and chemokines in the periphery and the central nervous system, and trigger a variety of neurobiological responses. Indeed, prior reports indicate that peripheral LPS administration in rats disrupts contextual fear memory consolidation processes, potentially due to elevated cytokine expression. We used a similar, but partially olfaction-based, contextual fear conditioning paradigm to examine the effects of LPS on memory consolidation and reconsolidation in mice. Additionally, interleukin-1ß (IL-1ß), brain-derived neurotrophic factor (BDNF), and zinc finger (Zif)-268 mRNA expression in the hippocampus and the cortex, along with peripheral cytokines and chemokines, were assessed. As hypothesized, LPS administered immediately or 2 h, but not 12 h, post-training impaired memory consolidation processes that support the storage of the conditioned contextual fear memory. Additionally, as hypothesized, LPS administered immediately following the fear memory trace reactivation session impaired memory reconsolidation processes. Four hours post-injection, both central cytokine and peripheral cytokine and chemokine levels were heightened in LPS-treated animals, with a simultaneous decrease in BDNF, but not Zif-268, mRNA. Collectively, these data reinforce prior work showing LPS- and cytokine-related effects on memory consolidation, and extend this work to memory reconsolidation.

Premature cognitive decline in specific domains found in young veterans with mTBI coincide with elder normative scores and advanced-age subjects with early-stage Parkinson's disease.

IMPORTANCE: Epidemiologists report a 56% increased risk of veterans with (+) mild traumatic brain injury (mTBI) developing Parkinson's disease (PD) within 12-years post-injury. The most relevant contributors to this high risk of PD in veterans (+) mTBI is unknown. As cognitive problems often precede PD diagnosis, identifying specific domains most involved with mTBI-related PD onset is critical. OBJECTIVES: To discern which cognitive domains underlie the mTBI-PD risk relationship proposed in epidemiology studies. DESIGN AND SETTING: This exploratory match-controlled, cross-sectional study was conducted in a medical school laboratory from 2017-2020. PARTICIPANTS: Age- and IQ-matched veterans with (+) and without mTBI, non-veteran healthy controls, and IQ-matched non-demented early-stage PD were compared. Chronic neurological, unremitted/debilitating diseases, disorders, dementia, and substance use among others were excluded. EXPOSURE: Veterans were or were not exposed to non-penetrating combat-related mTBI occurring within the past 7-years. No other groups had recent military service or mTBI. MAIN OUTCOMES / MEASURES: Cognitive flexibility, attention, memory, visuospatial ability, and verbal fluency were examined with well-known standardized neuropsychological assessments. RESULTS: Out of 200 volunteers, 114 provided evaluable data. Groups significantly differed on cognitive tests [F (21,299) = 3.09, p<0.0001]. Post hoc tests showed veterans (+) mTBI performed significantly worse than matched-control groups on four out of eight cognitive tests (range: p = .009 to .049), and more often than not performed comparably to early-stage PD (range: p = .749 to .140). CONCLUSIONS AND RELEVANCE: We found subtle, premature cognitive decline occurring in very specific cognitive domains in veterans (+) mTBI that would typically be overlooked in a clinic setting, This result potentially puts them at-risk for continual cognitive decline that may portend to the eventual onset of PD or some other neurodegenerative disease.

Sex differences in the impact of childhood socioeconomic status on immune function.

Early life stress increases one's risk for health problems later in life, and many studies find that these effects are sex-differentiated. Here, we examined relationships between multiple sources of early life stress and adult immune function in humans across several functional assays. Adult participants provided retrospective information about their childhood (a) socioeconomic status, (b) household unpredictability, and (c) exposure to adverse experiences. Participants' peripheral blood mononuclear cells (PBMCs) were then isolated for use in functional assays of immune performance: (a) tumor cell lysis by natural killer cells, (b) phagocytosis of Escherichia coli bioparticles, and (c) mitogen-induced leukocyte proliferation and cytokine release. In men, lower childhood socioeconomic status predicted decrements in immunological performance across functional assays, along with greater spontaneous cytokine release from PBMCs. These changes co-occurred with elevations in plasma testosterone levels. Similar effects were not observed for other sources of stress, nor were they found in women (with the exception of spontaneous cytokine release). These findings provide evidence that low childhood socioeconomic status has a lasting negative impact on multiple aspects of immune function, particularly in men.

Chronic sleep restriction increases soluble hippocampal Aß-42 and impairs cognitive performance.

Currently, over 44 million people worldwide suffer from Alzheimer's disease (AD). A common feature of AD is disrupted sleep. Sleep is essential for many psychological and physiological functions, though 35.3% of adults report getting less than 7 hours per night. The present research examined whether chronic sleep restriction would elevate hippocampal amyloid-beta1-42 expression or alter cognitive ability in adult C57BL/6 mice. Chronic sleep restriction was associated with cognitive impairment and increased hippocampal amyloid-beta. Thus, chronic sleep loss may have a detrimental effect upon cognitive function, in part, via increasing amyloid-beta levels in the hippocampus, even in non-genetically modified mice.

Inflammation Predicts Decision-Making Characterized by Impulsivity, Present Focus, and an Inability to Delay Gratification.

Here, we propose a novel theoretical model linking present-focused decision-making to the activities of the immune system. We tested our model by examining the relationship between inflammatory activity - in vivo and in vitro - and decision-making characterized by impulsivity, present focus, and an inability to delay gratification. Results support our model, revealing that inflammation predicts these outcomes even after controlling for factors that may contribute to a spurious linkage between them. Moreover, subsequent analyses revealed that our model was a better fit for the data than alternative models using present-focused decision-making and its health-harming behavioural sequelae (e.g., smoking, risky sexual behaviour) to predict inflammation, lending support for the proposed directionality of this relationship. Together, these results suggest that inflammation may contribute to decision-making patterns that can result in undesirable personal and societal outcomes.

Day length predicts investment in human immune function: Shorter days yield greater investment.

Winter is characterized by stressful conditions which compromise health and render animals more vulnerable to infection and illness than during other times of the year. Organisms are hypothesized to adapt to these seasonal stressors by increasing investment in immune function in response to diminished photoperiod duration. Here, we examined this hypothesis in a sample of healthy human participants. Using several functional immune assays in vitro, as well as by utilizing measures of in vivo proinflammatory cytokine levels, we predicted that shorter day length would be associated with greater investment in immunological function. Results revealed that shorter days predicted significant upregulation of several facets of immune function, including natural killer cell cytotoxicity, peripheral blood mononuclear cell proliferation (in response to, and in the absence of stimulation), and plasma levels of interleukin-6, as well as lower rates of Staphylococcus aureus growth in serum ex vivo. Further, consistent with the hypothesis that these trade-offs would be offset by decreased investment in mating effort, shorter day length also predicted lower levels of total testosterone in men. These results suggest that ambient photoperiod may be a powerful regulator of human immunological activity, providing some of the first evidence of seasonal changes in multiple facets of human immune function.

Influence of prenatal stress on behavioral, endocrine, and cytokine responses to adulthood bacterial endotoxin exposure.

Prior research suggests that prenatal stress, among other effects, can lead to hyper-reactivity of the offspring's hypothalamic-pituitary-adrenal (HPA) axis and alterations in immune function. These stress-induced changes have been linked to a greater propensity to develop depression or anxiety disorders. Furthermore, prenatally stressed offspring may be more susceptible to certain diseases. The immune alterations induced by prenatal stress exposure may disrupt the normal communication between the immune system, endocrine system, and central nervous system, potentially making prenatally stressed individuals more vulnerable to the negative aspects of immune activation, including cytokine-induced cognitive deficits and anxiety. The present study investigated whether prenatal stress would exaggerate these detrimental effects of peripheral immune activation. We hypothesized that prenatally stressed subjects would be hypersensitive to endotoxin administration and would therefore show exaggerated learning deficits, increased anxiety-like behavior, and increased peripheral and central interleukin-1beta (IL-1beta) levels. The observed results only partially supported our hypotheses, as prenatally stressed subjects showed evidence, albeit modest, of increased anxiety-like behavior following endotoxin administration relative to non-stressed controls. While prenatal stress exposure or lipopolysaccharide (LPS) administration independently impaired learning, the data failed to support the hypothesis that prenatally stressed subjects would show exaggerated cognitive deficits, engendered via enhanced peripheral and central IL-1beta levels, following immune activation. Collectively, the data suggest that although prenatal stress exposure led to increases in anxiety-like behavior following endotoxin exposure, it did not appear to increase susceptibility to LPS-induced cognitive decline or elevations in proinflammatory cytokine production.

Neonatal endotoxin exposure impairs avoidance learning and attenuates endotoxin-induced sickness behavior and central IL-1beta gene transcription in adulthood.

Infection during infancy, a time of critical neural development, may have long-term implications. Infection or exposure to an immune stimulus such as lipopolysaccharide (LPS) early in life leads to alterations in the reactivity of the hypothalamic-pituitary-adrenal axis (HPA) and febrile response in adulthood. Relatively few studies have assessed the behavioral and cognitive alterations induced by perinatal immune challenge. The data indicate that neonatal immune activation may alter adulthood behavior with, or sometimes without, subsequent adulthood exposure, depending on the study. The current study investigated the behavioral effects and IL-1beta transcription following intraperitoneal LPS administration on postnatal days (PNDs) 4 and 5, and subsequent LPS or saline administration in adulthood. Alterations in anxiety, motor behavior, and learning were assessed in male and female subjects. The results indicate that neonatal endotoxin exposure attenuated the LPS-induced decrease in motor behavior in female, but not male, subjects. Furthermore, perinatal immune activation disrupted avoidance learning in male, but not female, subjects in the absence of adulthood LPS administration. In addition, for male subjects, neonatal LPS exposure diminished central IL-1beta gene transcription following adulthood LPS administration. These findings indicate that perinatal endotoxin exposure may lead to alterations in the behavioral response to adulthood LPS administration, and provide evidence that early immune activation alone may trigger alterations in adulthood learning ability.

Behavioral immune system activity predicts downregulation of chronic basal inflammation.

Here, we present a mechanistically grounded theory detailing a novel function of the behavioral immune system (BIS), the psychological system that prompts pathogen avoidance behaviors. We propose that BIS activity allows the body to downregulate basal inflammation, preventing resultant oxidative damage to DNA and promoting longevity. Study 1 investigated the relationship between a trait measure of pathogen avoidance motivation and in vitro and in vivo proinflammatory cytokine production. Study 2 examined the relationship between this same predictor and DNA damage often associated with prolonged inflammation. Results revealed that greater trait pathogen avoidance motivation predicts a) lower levels of spontaneous (but not stimulated) proinflammatory cytokine release by peripheral blood mononuclear cells (PBMCs), b) lower plasma levels of the proinflammatory cytokine interleukin-6 (IL-6), and c) lower levels of oxidative DNA damage. Thus, the BIS may promote health by protecting the body from the deleterious effects of inflammation and oxidative stress.

Age increases vulnerability to bacterial endotoxin-induced behavioral decrements.

Peripheral lipopolysaccharide (LPS) or proinflammatory cytokines produce alterations in learning, memory, and other behaviors. Additionally, research has demonstrated that factors such as dose, route of administration, species, strain, gender, and age are important modulatory factors in the effects of endotoxin exposure. Previous research from our laboratory and others indicate that LPS-induced behavioral deficits are greater in older subjects. The current study examined avoidance learning in a negatively reinforced operant procedure (i.e., two-way active avoidance conditioning) following single or repeated intraperitoneal LPS injections in 2- and 12-month-old male C57BL/6J mice. LPS-treated subjects show impaired acquisition of the task regardless of the age of the subject, as these animals performed significantly fewer avoidance responses than controls. However, the effects of LPS administration were more pronounced in the 12-month-old animals, particularly for the subjects given repeated LPS injections. These results support the hypothesis that endotoxin exposure is capable of altering performance in this task in a way that may reflect deficits in learning, and provide evidence that increased age may exacerbate these deleterious behavioral effects.

Effects of intraperitoneal lipopolysaccharide on Morris maze performance in year-old and 2-month-old female C57BL/6J mice.

Several studies have shown that systemic lipopolysaccharide (LPS) or interleukin-1beta (IL-1beta) may affect performance in various learning tasks, including the Morris water maze. In the current study, female C57BL/6J mice, either 2 months or 1 year of age, were given 5 days of testing followed by 3 days of rest, and then three additional days of testing. Mice either received a single LPS injection on day 1 and saline on days 2-5, LPS injections on days 1-5, or saline injections on days 1-5. Daily LPS administration significantly prolonged latency for the animals to find the platform, and decreased their swimming speed. Year-old mice treated with LPS each day also exhibited significantly higher levels of thigmotaxis in the maze. Despite effects on latency and swim speed, no effect of LPS treatment was observed for distance traveled to the platform or other measures that clearly indicate disruption of learning in the maze. On the other hand, age was a significant factor affecting both latency and distance, with older animals swimming greater distances to find the platform. Additionally, older animals were more adversely affected by daily LPS treatment. In this study, although LPS-induced performance impairments in the Morris water maze were noted, particularly in older animals, these effects were not clearly indicative of learning impairment per se.

Bacterial endotoxin-induced behavioral alterations in two variations of the Morris water maze.

Several studies report that lipopolysaccharide (LPS) or interleukin-1beta (IL-1beta) may affect behavior in a variety of learning tasks, including the Morris water maze (MWM), though the nature of these effects varies with testing parameters. The present study used C57BL/6J mice to evaluate the effect of a single intraperitoneal LPS injection 4 h prior to day 1 of testing, LPS before each day of testing, or saline prior to each test day, on performance in two variations of the MWM. In the first experiment, one that utilized a standard hidden platform, LPS clearly affected performance, as shown by increased latencies and greatly decreased swimming speeds. However, a modest effect on distance swam was only present during later test days. These data show a clear deficit in performance (driven by decreased swim speed), and some evidence for learning decrements on later test days. To explore to what degree the effects of LPS in the water maze were the result of alterations in performance factors such as motor behavior, a second experiment was conducted in which a highly visible jet-black platform was utilized. Despite eliminating the need for spatial learning, mice administered LPS still exhibited significantly increased latency scores and decreased swim speed. However, there was no difference between treatment groups in distance swam. These results reinforce the idea that, even when present, potential learning effects of LPS may sometimes be difficult to untangle from performance effects unrelated to learning, and underscore the need for utilizing behavioral tests that offer suitable control for LPS-induced performance effects.

Peripheral lipopolysaccharide administration impairs two-way active avoidance conditioning in C57BL/6J mice.

Peripheral administration of lipopolysaccharide (LPS) or interleukin-1 (IL-1) may lead to alterations of CNS function and behavioral changes designated "sickness behavior." Further, some experiments show evidence of LPS- and cytokine-mediated alterations in learning and memory. The current series of experiments examined the effects of a single or repeated intraperitoneal LPS injections, at a number of doses and time points before or after test sessions, on behavior in a two-way active avoidance conditioning paradigm. Subjects were able to avoid the mild shock stimulus, escape it, or fail to respond to it. Subjects treated with LPS at many, but not all, of the time points sampled showed impaired learning, by exhibiting significantly fewer avoidance responses than controls. Furthermore, an LPS-induced increase in non-cued inter-trial interval crossings was observed during the later days of testing, suggesting that a greater percentage of their avoidance responses was not conditioned and their behavior was less efficient. Taken together, the results suggest that LPS-treated animals showed a diminished association between conditioned stimulus (CS) and unconditioned stimulus (US). These results support the theory that peripheral immune stimuli may induce deleterious effects on learning, and extend the work to a negatively reinforced operant procedure.

Peripheral administration of poly I:C leads to increased hippocampal amyloid-beta and cognitive deficits in a non-transgenic mouse.

Alzheimer's disease (AD) is a progressive disorder characterized by neuronal and behavioral deterioration. Two hallmark pathologies of AD are amyloid-beta (Aß) plaques and neurofibrillary tangles, and the presence of such pathology can limit cell-to-cell communication, leading to cognitive deficits, and neuronal cell death. Although Aß plaques were originally thought to cause the cognitive deficits, more simple forms of Aß, such as monomers, dimers, tetramers and oligomers, have also been shown to be neurotoxic. Moreover, chronic inflammation has also been implicated in the onset and progression of these AD-related pathologies. The current study was designed to further our understanding of peripheral inflammation-induced AD-like pathology, by administering polyinosinic:polycytidylic acid (poly I:C), a viral mimetic. Mice were administered intraperitoneal injections of poly I:C or saline once daily for 7 consecutive days. Hippocampal tissue from animals receiving poly I:C contained significantly higher levels of the Aß1₋42 peptide. Even after ensuring that potential sickness behavior could not confound cognitive testing, we found that animals administered poly I:C displayed significant cognitive deficits in the hippocampus-dependent contextual fear conditioning paradigm. These results confirm our hypothesis that peripheral inflammation can lead to increased levels of hippocampal-Aß and associated cognitive deficits.

Peripheral administration of D-cycloserine rescues memory consolidation following bacterial endotoxin exposure.

In the current study, the partial NMDA receptor agonist D-cycloserine (DCS) rescued memory consolidation following systemic bacterial endotoxin exposure. DCS failed, however, to restore hippocampal BDNF mRNA levels that were diminished following a systemic administration of LPS, and did not alter NR1 or NR2C NMDA receptor subunit expression. These results extend prior research into the role of DCS in neural-immune interactions, and indicate that the detrimental effects of peripheral LPS administration on consolidation of contextual fear memory may be ameliorated with DCS treatment, though the mechanisms underlying these effects are currently unclear.

Age exacerbates sickness behavior following exposure to a viral mimetic.

Poly I:C, a viral mimetic, is a synthetic double-stranded RNA that is known to cause activation of the innate immune system, resulting in the emergence of sickness behaviors in otherwise healthy adult mice. However, the way in which such effects of poly I:C manifest themselves in aged mice are not currently known. We hypothesized that poly I:C administration would lead to burrowing deficits, but that these deficits would be exaggerated in aged subjects (19-months old) compared to young subjects (4-months old) that received the same dose. In order to associate these behavioral decrements with inflammatory factors, we measured mRNA expression of IL-1ß and IL-6 in the hippocampus and parietal cortex and peripheral protein expression of IL-6, TNF-α, MCP-1, MIP-1α, and IL-1ß in the serum. After exposure to poly I:C, aged subjects demonstrated significant impairments in their burrowing behavior, compared to younger subjects administered the same dose. These behavioral decrements coincided with increased expression of IL-6 among animals exposed to poly I:C and increased expression of IL-1ß among aged animals in the hippocampus and cortex. Furthermore, we observed an increase in peripheral poly I:C-induced IL-6, TNF-α, MCP-1, and MIP-1α, but not IL-1ß. These results indicate that virus-mediated immune activation in the aging body can lead to increased sickness behavior. Furthermore, these data indicated a possible dissociation between the effects of poly I:C on sickness behaviors in aged mice, with central expression of IL-1ß potentially playing a role in age-related impairments.